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Biomedical subjects

C F Stewart

Publications and source records attributed to C F Stewart.

At least 37 records · Page 2Linked to original sources
PubMed1998

Phase I study of DMP 840 in pediatric patients with refractory solid tumors.

The bis-naphthalimide DMP 840 has demonstrated high level antitumor activity in a number of preclinical models and has been evaluated in several Phase I studies in adults. We enrolled 10 patients with refractory pediatric solid tumors to this Phase I study of DMP 840 given intravenously by short infusion daily for 5 days. The most frequent and dose-limiting toxicity was myelosuppression. The maximum tolerated dose on this schedule was 8.6 mg/m2 daily for 5 days. One patient had a complete response; there were no measurable tumor responses among the remaining 9 patients.

Adolescent↗
PubMed1998

Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients.

OBJECTIVES: This paper reviews a 12-year experience in more than 900 patients with spasmodic dysphonia who have been treated with botulinum toxin. STUDY DESIGN: This is a retrospective analysis of patients with adductor spasmodic dysphonia (strain-strangled voice), abductor spasmodic dysphonia (whispering voice), and adductor breathing dystonia (paradoxical vocal fold motion), all of whom have been treated with botulinum toxin injections for relief of symptom. METHODS: All of the patients were studied with a complete head and neck and neurologic examination; fiberoptic laryngostroboscopy; acoustic and aerodynamic measures; and a speech evaluation including the Universal spasmodic dysphonia rating scale. Some were given electromyography. All patients received botulinum toxin injections into the affected muscles under electromyographic guidance. RESULTS: The adductor patients had an average benefit of 90% of normal function lasting an average of 15.1 weeks. The abductor patients had an average benefit of 66.7% of normal function lasting an average of 10.5 weeks. Adverse effects included mild breathiness and coughing on fluids in the adductor patients, and mild stridor in a few of the abductor patients. CONCLUSION: Botulinum toxin A injection of the laryngeal hyperfunctional muscles has been found over the past 12 years to be the treatment of choice to control the dystonic symptoms in most patients with spasmodic dysphonia.

Adult↗
PubMed1998

Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric Oncology Group Study.

PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity of topotecan when combined with cyclophosphamide in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS: A total of 33 patients received cyclophosphamide (250 mg/m2/dose) followed by topotecan in escalating doses (0.6 to 0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. A total of 154 fully assessable treatment courses were given to these patients. RESULTS: Neutropenia was the dose-limiting toxicity of the therapy at both topotecan dose levels. The addition of filgrastim allowed escalation of the topotecan dose to the 0.75-mg/m2 level with acceptable neutropenia. Other significant toxicities were anemia and thrombocytopenia. Nonhematopoietic toxicity of grades > or = 3 was not observed. Responses were reported in patients with Wilms' tumor (one complete response [CR], one partial response [PR]), neuroblastoma (one CR, one PR), rhabdomyosarcoma (one PR), and osteosarcoma (one PR). Pharmacokinetic studies indicate that cyclophosphamide administered on the schedule used in this study did not alter topotecan disposition on day 5. As with previous studies, a pharmacodynamic relation between systemic exposure and myelosuppression was noted. CONCLUSION: The combination of topotecan and cyclophosphamide shows activity in a wide variety of pediatric solid tumors and can be given with acceptable hematopoietic toxicity with the use of filgrastim support. We recommend that pediatric phase II trials use cyclophosphamide 250 mg/m2 followed by topotecan 0.75 mg/m2 daily for 5 days with filgrastim for amelioration of neutropenia.

Adolescent↗
PubMed1998

Probenecid alters topotecan systemic and renal disposition by inhibiting renal tubular secretion.

Topotecan is primarily eliminated by the kidneys, with 60 to 70% of the dose recovered as topotecan total in the urine. To elucidate the mechanisms of topotecan renal clearance, we evaluated the effect of probenecid on topotecan renal and systemic disposition in mice. Topotecan lactone or hydroxy acid (1.25 mg/kg i.v.) was administered alone or in combination with probenecid (600 or 1,200 mg/kg) given by oral gavage 30 min before and 3 hr after topotecan. Serial blood samples (three mice per time point) and urine samples (five mice per treatment arm) were collected during a 6-hr period. Compared with topotecan alone, coadministration of topotecan lactone or hydroxy acid with probenecid (600 mg/kg) decreased topotecan lactone, total, and hydroxy acid systemic clearance, and total renal clearance. The predominant effect of probenecid was to increase hydroxy acid area under the plasma concentration time curve after administration of topotecan lactone (238.8 vs. 109.9 ng.hr/ml alone, P < .05), or hydroxy acid (1297.2 vs. 355.0 ng.hr/ml alone, P < .05). By inhibiting renal tubular secretion, probenecid decreased renal and systemic clearance which led to an increase in topotecan systemic exposure. These data suggest that probenecid primarily inhibited secretion of the anionic hydroxy acid form, and by direct or indirect mechanisms increased topotecan lactone systemic exposure. Topotecan elimination through renal tubular secretion may have clinical relevance for the use of topotecan in patients with altered renal function.

Animals↗
PubMed1998

Altered irinotecan and SN-38 disposition after intravenous and oral administration of irinotecan in mice bearing human neuroblastoma xenografts.

The antitumor activity of irinotecan in vitro primarily results from its hydrolysis by carboxylesterase to the active metabolite SN-38. The present study was conducted to evaluate the effect of human neuroblastoma xenografts on irinotecan and SN-38 disposition after i.v. and oral irinotecan administration. Non-tumor-bearing mice and mice bearing three different human neuroblastoma xenograft lines (NB1691, NB1643, and NBEB) were given irinotecan (10 mg/kg) by short i.v. injection into the tail vein or by oral gavage. Serial plasma samples were obtained, processed to isolate irinotecan and SN-38 lactone, and assayed with a sensitive and specific high-performance liquid chromatography assay. Noncompartmental and compartmental pharmacokinetic analyses were performed. A four-compartment model was used for analysis of irinotecan and SN-38 concentration-time data after i.v. administration. The presence of tumor increased irinotecan systemic exposure (1.2-3.8-fold; P < 0.05) after i.v. and oral administration in mice bearing neuroblastoma xenografts compared to non-tumor-bearing mice. Moreover, SN-38 systemic exposures were higher (1.3-3.8-fold; P < 0.05) in mice bearing human neuroblastoma xenografts as compared to non-tumor-bearing mice, with the greatest effect observed after oral administration of irinotecan. A schematic model is presented to provide a mechanistic basis for our observations. These results emphasize the need to perform preclinical pharmacokinetic studies to evaluate the influence of tumor on drug disposition.

Administration, Oral↗
PubMed1998

Studies of the efficacy and pharmacology of irinotecan against human colon tumor xenograft models.

Irinotecan, administered i.v. on days 1-5 and 8-12 [(dx5)2 i.v.] has demonstrated significant activity against advanced human tumor xenografts. To explore the feasibility of prolonged oral administration of irinotecan, we compared the efficacy of oral and i.v. irinotecan on the (dx5)2 schedule. We also evaluated oral therapy for 12 consecutive weeks [(dx5)12] at 25 and 50 mg/kg and two consecutive 5-day courses repeated every 21 days for up to four cycles ([(dx5)2]4) at 50 and 75 mg/kg/dose in a series of human colon carcinoma xenograft lines. In addition, we evaluated the effect of a sensitive (HC1) and resistant (ELC2) human colon adenocarcinoma xenograft on irinotecan and SN-38 lactone disposition after administration of irinotecan 10 mg/kg i.v. and 10 and 25 mg/kg p.o. Irinotecan i.v. at 40 mg/kg and oral at 50 and 75 mg/kg on the (dx5)2 schedule had similar activity against the panel of adult colon adenocarcinoma xenografts. Irinotecan given p.o. also demonstrated significant activity against a topotecan-resistant derivative, VRC5/TOPO. Oral administration of 75 mg/kg [(dx5)2]4 and 50 mg/kg (dx5)12 achieved complete response in five of seven xenograft lines evaluated. After i.v. administration, mice bearing HC1 xenografts had 43% greater SN-38 lactone systemic exposure compared to those with ELC2 xenografts and non-tumor-bearing mice. After oral (10 mg/kg) administration, there was a 5-fold higher molar formation of SN-38 lactone compared to i.v. (10 mg/kg) administration in tumor and non-tumor-bearing mice. SN-38 systemic exposure associated with the lowest oral dose (25 mg/kg) achieving complete response for HC1 was 942.6 ng/ml x h. These results emphasize the importance of pharmacokinetic studies as part of tumor response studies in xenograft models.

Adenocarcinoma↗
PubMed1998

Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma.

Topotecan undergoes both renal and hepatic elimination, with topotecan urinary recovery ranging from 60 to 70%. We evaluated the potential of phenytoin to alter the disposition of topotecan and its N-desmethyl metabolite. A 5-year-old child with high-risk medulloblastoma received the first course of topotecan with phenytoin and the second course without phenytoin. For both courses, topotecan doses were adjusted to achieve a target topotecan lactone plasma area under the curve (AUC). Serial plasma samples were obtained, and lactone and total plasma concentrations of topotecan, as well as total plasma and cerebrospinal fluid concentrations of N-desmethyl topotecan, were measured by high-performance liquid chromatography. Phenytoin coadministration increased lactone and total topotecan clearance from 43.4 +/- 1.9 L/h/m2 to 62.9 +/- 6.4 L/h/m2, and 20.8 +/- 2.8 L/h/m2 to 30.6 +/- 4.1 L/h/m2, respectively (P < 0.05). Concomitant phenytoin increased the plasma AUC of total N-desmethyl topotecan from 7.5 +/- 0.68 ng/ml x h to 16.3 +/- 0.53 ng/ml x h (P < 0.05) at plasma AUC of total topotecan of 226.0 +/- 5.5 ng/ml x h and 240.9 +/- 39.8 ng/ml x h, respectively. N-Desmethyl topotecan penetrated into the cerebrospinal fluid (0.12 +/- 0.01). The patient experienced no grade 3 or 4 toxicity. These are the first data documenting altered topotecan and N-desmethyl topotecan disposition when coadministered with phenytoin and suggests that topotecan may undergo further hepatic metabolism. Although there is an increase in exposure to the active N-desmethyl topotecan metabolite, it is less than the decrease in exposure to topotecan lactone. Therefore, patients concomitantly administered phenytoin may require an increase in topotecan dose to achieve a similar pharmacological effect as a patient not receiving phenytoin.

Anticonvulsants↗
PubMed1998

Effective schedules of exposure of medulloblastoma and rhabdomyosarcoma xenografts to topotecan correlate with in vitro assays.

The camptothecin derivative topotecan has been postulated to mediate its antitumor effect through a drug-induced increase in covalent topoisomerase I-DNA complexes. If this hypothesis is correct, then schedules of exposure to topotecan that maximize the number of topoisomerase I-DNA complexes should produce the greatest cytotoxicity. We identified schedules of exposure to topotecan that maximize levels of complexes in vitro and used these schedules to postulate effective schedules of exposure in vivo in a mouse xenograft model. Unexpectedly, K+-SDS precipitation assays quantitating covalent topoisomerase I-DNA complexes showed that Daoy medulloblastoma and Rh30 rhabdomyosarcoma cells became refractory to drug-induced increases in complexes after an 8-h exposure to 2.5 microM topotecan. In contrast, assays using 10-50 nM topotecan showed that the cells did not become refractory, and more importantly, intermittent exposure to drug increased the level of complexes approximately 2-fold above the maximum level observed after a single drug exposure. The data indicate that continuous exposure to topotecan does not maximize topoisomerase I-DNA complexes and suggest that effective intermittent schedules of exposure to topotecan might be identified. Growth inhibition assays confirmed this hypothesis and showed that growth inhibition by topotecan was extremely schedule dependent in Rh30 cells but not in Daoy cells. Xenograft studies showed that schedules modeled after the in vitro experiments produced complete tumor regressions in mice. Topotecan given daily (0.6-2.2 mg/kg) or every other day (1-3.3 mg/kg) for 2 weeks, repeated every 21 days for three cycles, produced complete regressions of Daoy xenografts; however, daily exposure was required to achieve complete regressions of Rh30 xenografts. We conclude that effective intermittent schedules of exposure to topotecan, based on biochemical parameters, can be identified. The clinical utility of each schedule will depend on the relative antitumor effect compared to the toxic effect on the bone marrow, which usually limits administration of topotecan to patients.

Animals↗
PubMed1998

Extending principles learned in model systems to clinical trials design.

Clinical results with irinotecan (CPT-11 [Camptosar]) and other camptothecin derivatives in various cancers, although encouraging, have fallen short of the expectations predicted by preclinical models. One proposed explanation for this is that preclinical xenograft models do not predict for the sensitivity of human cancer. In this article, we describe the results of several studies suggesting that this explanation is incorrect. Instead, our results indicate that the discrepancy between clinical response rates and findings in preclinical models may be due to a failure to incorporate the principles learned from preclinical studies into the design of clinical trials. Our analysis suggests that if differences in host tolerance are taken into account, the xenograft models are quite accurate predictors of clinical response. Moreover, application of the principles derived from preclinical models to the design of clinical trials may significantly enhance clinical response rates. Thus, the camptothecin analogs provide a paradigm for better integrated, pharmacokinetically driven, preclinical and clinical development of new drugs.

Animals↗
PubMed1998

A four-hour topotecan infusion achieves cytotoxic exposure throughout the neuraxis in the nonhuman primate model: implications for treatment of children with metastatic medulloblastoma.

The purpose of this study was to define the length of topotecan (TPT) i.v. infusion necessary to attain a cytotoxic exposure for medulloblastoma cells throughout the neuraxis. In vitro studies of human medulloblastoma cell lines (Daoy, SJ-Med3) were used to estimate the length and extent of TPT systemic exposure associated with inhibition of tumor cell growth or the exposure duration threshold (EDT). We evaluated TPT systemic and cerebrospinal fluid (CSF) disposition in six male rhesus monkeys (8-12 kg) that received TPT 2.0 mg/m2 i.v. as a 30-min or 4-h infusion. Plasma and CSF samples were assayed for TPT lactone by high-performance liquid chromatography, and the CSF exposures were compared with the estimated EDT. Results of the in vitro studies defined an EDT as a TPT lactone concentration of > 1 ng/ml for 8 h (IC99) daily for 5 days. The mean +/- SD for systemic clearance (CL(SYS)), penetration into fourth ventricle (%CSF(4th)), and penetration into lumbar space (%CSF(LUM)) were similar for the 30-min and the 4-h infusions. At a TPT lactone systemic exposure (AUC(PL)) of 56.7 +/- 19.9 ng/ml x h, time above 1 ng/ml in the fourth ventricle was 1.4-fold greater for a 4-h infusion compared with a 30-min infusion. At a TPT lactone AUC(PL) of 140 ng/ml x h, the 4-h infusion achieved the desired TPT exposure throughout the neuraxis (lateral and fourth ventricles and lumbar space), whereas the 30-min infusion failed to achieve it in the lumbar space. In conclusion, prolonging TPT i.v. infusion from 30-min to 4-h at a targeted AUC(PL) achieves the EDT throughout the neuraxis and represents an alternative method of TPT administration that will be tested prospectively in patients with high-risk medulloblastoma.

Animals↗
PubMed1998

Conversion of the CPT-11 metabolite APC to SN-38 by rabbit liver carboxylesterase.

The anticancer drug CPT-11 (7-ethyl-[4(1-piperidino)-1-piperidino]carbonyloxycamptothecin) is a water-soluble derivative of camptothecin. We report here the conversion of APC (7-ethyl-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin), an inactive metabolite of CPT-11, to SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of CPT-11, by a rabbit liver carboxylesterase. This reaction is not catalyzed by any known human enzyme. The formation of SN-38 from APC was characterized by an apparent Km of 37.9 +/- 7.1 microM and a Vmax of 16.9 +/- 0.9 pmol/units/min. SN-38 was confirmed as a reaction product by high-performance liquid chromatography and mass spectrometry. A 24-h incubation of 10 microM APC with 500 units/ml of rabbit carboxylesterase produced 4 microM SN-38. The product of this reaction inhibited the growth of U373 MG human glioblastoma cells in vitro. The IC50 for a 24-h exposure of U373 MG cells to APC in the presence of 50 units/ml of rabbit carboxylesterase was 0.27 +/- 0.08 microM, whereas APC alone demonstrated no inhibition of growth at concentrations up to 1 microM. The IC50 of U373 MG cells transfected with the cDNA encoding the rabbit carboxylesterase (U373pIRESrabbit) and exposed to APC for 24 h was 0.8 +/- 0.1 microM APC, whereas the growth of cells transfected with vector control (U373pIRES) was unaffected by up to 1 microM APC. Because APC is nontoxic to human cells, we are investigating the possibility of using APC/rabbit carboxylesterase in a prodrug/enzyme therapeutic approach.

Animals↗
PubMed1997

Disposition of irinotecan and SN-38 following oral and intravenous irinotecan dosing in mice.

The present study was conducted to quantitate the disposition of irinotecan lactone and its active metabolite SN-38 lactone in mice following oral and intravenous administration, and to evaluate the systemic exposure of irinotecan lactone and SN-38 lactone associated with antitumor doses of irinotecan lactone in mice bearing human tumor xenografts. Nontumor-bearing mice were given a single oral or intravenous irinotecan dose (5, 10, 40, or 75 mg/kg), and serial plasma samples were subsequently obtained. Irinotecan and SN-38 lactone plasma concentrations were measured using an isocratic HPLC assay with fluorescence detection. The disposition of intravenous irinotecan lactone was modeled using a two-compartment pharmacokinetic model, and the disposition of oral irinotecan and SN-38 lactone was modeled with noncompartmental methods. Irinotecan lactone showed biphasic plasma disposition following intravenous dosing with a terminal half-life ranging between 1.1 to 3 h. Irinotecan lactone disposition was linear at lower doses (5 and 10 mg/kg), but at 40 mg/kg irinotecan lactone clearance decreased and a nonlinear increase in irinotecan lactone AUC was observed. The steady-state volume of distribution ranged from 19.1 to 48.1 l/m2. After oral dosing, peak irinotecan and SN-38 lactone concentrations occurred within 1 h, and the irinotecan lactone bioavailability was 0.12 at 10 mg/kg and 0.21 at 40 mg/kg. The percent unbound SN-38 lactone in murine plasma at 1000 ng/ml was 3.4 +/- 0.67%, whereas at 100 ng/ml the percent unbound was 1.18 +/- 0.14%. Irinotecan and SN-38 lactone AUCs in micebearing human neuroblastoma xenografts were greater than in nontumor-bearing animals. Systemic exposure to unbound SN-38 lactone in nontumor-bearing animals after a single oral irinotecan dose of 40, 10, and 5 mg/kg was 28.3, 8.6, and 2.9 ng h/ml, respectively. Data from the present study provide important information for the design of phase I studies of oral irinotecan.

Administration, Oral↗
PubMed1997

Adductor spasmodic dysphonia: standard evaluation of symptoms and severity.

Description and quantification of the symptoms of adductor spasmodic dysphonia often reflect the clinician's knowledge of the disorder, ideas about the cause of the disorder, and personal experience. No reliable instrument that identifies and quantifies the spectrum of perceptual symptoms has been available. Therefore, we developed a standardized measure called the Unified Spasmodic Dysphonia Rating Scale (USDRS) in cooperation with a team of 118 experienced voice judges. Consensual validations of content validity guided the incremental development of the scale. Using the USDRS allows more consistent and complete data collection, both clinically and in research clinical trials.

Humans↗
PubMed1997

Efficacy of oral irinotecan against neuroblastoma xenografts.

The efficacy of the topoisomerase I inhibitor, 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptotheci n (irinotecan, CPT-11), administered by oral gavage has been examined against a panel of six independently derived neuroblastoma xenografts. Irinotecan was administered either daily for 5 days on 12 consecutive weeks ¿(d x 5)12¿ or for 5 days on two consecutive weeks repeated every 21 days for 4 cycles ¿[(d x 5)2]4¿. Given on the (d x 5)12 schedule the maximum tolerated dose (MTD) was 50 mg/kg. For intermittent scheduling ¿[(d x 5)2]4¿, the MTD was 75 mg/kg, resulting in the same total dose being administered (3 g/kg) over the period of treatment. At the MTD for the 12 consecutive week schedule there were two of 42 toxicity related deaths, whereas intermittent scheduling at the MTD resulted in none of 42 deaths. The intermittent schedule ¿[(d x 5)2]4¿ was less toxic than therapy given (d x 5)12, as at the end of treatment mice weighed 92 +/- 4% (SD; n = 6 experiments) and 81 +/- 4% (SD; n = 6 experiments) of their body weight at the start of therapy, respectively. The latter schedule was associated with loose feces starting around week 8 of therapy, broken teeth and a high incidence of swelling of the orbital conjunctiva that developed late in the course of therapy. Given (d x 5)12, irinotecan caused complete regressions of all six neuroblastoma xenograft lines. Because mice tolerate significantly greater systemic exposure to SN-38 lactone than do patients (as determined by plasma AUC at the respective MTD), we evaluated the intermittent schedule of administration, reducing the dose/administration to determine the lowest dose levels that produced objective regressions of these neuroblastoma xenografts and determined the daily systemic exposure associated with these dose levels. In four lines examined objective responses were obtained at dose levels of 12.5 or 6.25 mg/kg. The daily plasma AUC exposures associated with minimum dose achieving response in NB1691 (12.5 mg/kg), NB1643 (6.25 mg/kg) and NBEB (12.5 mg/kg) for irinotecan lactone were 219, 152 and 653 ng-h/ml, respectively; and for SN-38 lactone were 704, 418 and 987 ng-h/ml, respectively. These results indicate that childhood neuroblastoma xenografts are highly sensitive to irinotecan given by oral administration and therapeutic activity is similar to i.v. irinotecan administered on similar schedules.

Administration, Oral↗
PubMed1997

Efficacy of systemic administration of irinotecan against neuroblastoma xenografts.

The efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptotheci n (irinotecan, CPT-11) has been examined against a panel of six independently derived neuroblastoma xenografts. Intensive courses of therapy, where irinotecan was administered i.v. daily 5 days per week for two consecutive weeks [(dx5)2; defined as 1 cycle], were compared to more protracted low-dose schedules where cycles were repeated every 21 days for a total of three courses ¿abbreviated [(dx5)2]3¿. When administered (dx5)2 for a single cycle, the maximum tolerated daily dose was 40 mg/kg. Irinotecan induced a high frequency of complete regressions (CRs) in four of the six lines examined; however, most tumors achieving CR regrew during the period of observation (12 weeks). Furthermore, there was no advantage in high-dose regimens as compared to low dose (10 mg/kg) on the same schedule. Protracted schedules of administration, where three courses of therapy were given at 21-day intervals ¿[(dx5)2]3¿ i.v. were examined at 10 and 5 mg/kg/dose. Even at the lower dose level, irinotecan caused 100% CR in all tumor lines that were maintained at 12 weeks. To determine the minimum dose levels required to induce objective regressions of neuroblastoma xenografts, decreasing doses were examined using the [(dx5)2]3 i.v. schedule. At 2.5 mg/kg/dose, >90% of NB-1643, NB-1691, NB-1382.2, and NB-EB xenografts demonstrated CR, whereas at 1.25 mg/kg/dose, all six tumor lines evaluated demonstrated objective regressions (>/=50% volume reduction), with a high frequency of CRs in four tumor lines. The 10-hydroxy-7-ethyl CPT lactone single-day systemic exposure measured with the minimum dose (2.5 mg/kg) associated with complete response was 198, 257, and 228 ng.h/ml for mice bearing NB-1643, NB-1691, and NB-EB tumors, respectively. These results indicate that childhood neuroblastoma xenografts are highly sensitive to irinotecan given by parenteral administration, and that efficacy is schedule dependent.

Animals↗
PubMed1996

Topoisomerase I interactive drugs in children with cancer.

Topotecan, irinotecan, and 9-aminocamptothecin (9-AC) are analogs of the plant alkaloid 20(S)-camptothecin (CMT), the prototypical DNA topoisomerase I interactive agent. These agents interact with the topoisomerase I-DNA complex and prevent resealing topoisomerase I-mediated DNA single-strand breaks. This eventual leads to double-strand DNA breaks and apoptosis or cell death. Topotecan, irinotecan, and 9-AC have shown significant activity in mice bearing pediatric solid tumor xenografts; the greatest antitumor responses were found with protracted continuous schedules. Preclinical data also suggest that maintenance of an exposure-duration threshold (EDT) may be required to achieve optimal cytotoxicity. Pediatric Phase I trials have evaluated the toxicity and safety to camptothecin analogs in children with relapsed solid tumors and relapsed acute leukemia. The primary dose-limiting toxicity (DLT) for the CMT analogs in children has been myelosuppression, except for mucositis observed with the 120-hr continuous topotecan infusion schedule. Pharmacodynamic relationships with these analogs have been reported between systemic exposure, and myelosuppression and mucositis. Although not a primary objective of the early Phase I studies, antitumor responses have been reported. In this review, the pharmacokinetic and pharmacodynamics of the CMT analogs studied in children are summarized, and future studies of these agents are discussed.

Animals↗